Alloantibodies in Cardiac Transplantation - Intervention, Outcomes and Mechanisms

描述（申请人提供）：描述（申请人提供）： 针对同种异体移植抗原的抗体越来越被认为是成人同种异体移植结局的关键决定因素。小儿心脏移植候选人经常基于先前暴露于血液制品和同种移植物而致敏。为了克服等待名单上的高死亡率，最近在几个儿科中心进行了跨供体特异性交叉配型的移植，早期结果令人鼓舞。该申请汇集了六个领先的心脏移植中心和领先的移植科学家，研究预先形成和从头同种抗体对儿科心脏移植结果的影响。具体目标1将在380名儿科移植候选人的连续队列中定义抗HLA和云母同种抗体的流行率、滴度和抗原特异性。将确定其发展的风险因素。具有预先形成的抗HLA抗体和阳性供体特异性交叉配型的候选人将进入多中心、非随机治疗试验，以评价统一管理方案的安全性和有效性（特定目标2）。该方案将涉及术中和术后血浆置换/置换和统一的免疫抑制方案。主要终点将是移植后一年内无死亡、移植物丢失和排斥反应伴血流动力学损害的患者比例。我们假设75%的患者将达到该终点。将在统一免疫抑制方案（特定目标3）下，在前瞻性观察方案中对非致敏候选患者进行研究，以确定新发抗HLA和抗云母抗体的患病率。我们推测，新生抗体的发展将是一个独立的预测更频繁和严重的急性排斥反应。在具体目标4中，将进行机制研究，以寻求解释为什么一些儿童发生移植物损伤，而其他儿童在存在阳性供体特异性交叉配型的情况下似乎“适应”其移植物。我们假设三个相互关联的因素有助于移植物的调节：1）。抗体的特征2）.内皮细胞对抗体介导的损伤的抵抗力和3）。供体血管内皮细胞被受体来源的血管内皮细胞替代导致内皮嵌合体。最后，我们将研究一种非侵入性体液排斥反应标志物的发展;细胞结合补体激活产物的定量测量。CTOT-C提供了一个理想的机制，进行拟议的研究，并应导致重要的新知识抗体介导的移植物损伤在小儿心脏移植。这将为该领域未来临床试验的设计提供急需的信息。相关性：小儿心脏移植仍然是姑息性的，再次移植的需求很高，经济和社会负担很大。所有能够提高同种异体移植物存活率的策略都将改善这些儿童的健康状况，并减轻有限供体库的负担。

DESCRIPTION (provided by applicant): DESCRIPTION (provided by applicant): Antibodies directed against allograft antigens are being increasingly recognized as critical determinants of allograft outcomes in adults. Pediatric heart transplant candidates are frequently allosensitized based on prior exposure to blood products and homografts. To overcome the high wait-list mortality, transplantation across a donor-specific cross-match has recently been performed in several pediatric centers, with early encouraging results. This application brings together a group of six leading heart transplant centers and leading transplantation scientists to study the impact of preformed and de novo alloantibodies on pediatric heart transplant outcomes. Specific Aim 1 will define the prevalence, titer and antigen specificities of anti- HLA and MICA alloantibodies, in a consecutive cohort of 380 pediatric transplant candidates. Risk factors for their development will be determined. Candidates with preformed anti-HLA antibodies and a positive donor- specific cross-match will enter into a multi-center, non-randomized treatment trial to evaluate the safety and efficacy of a uniform protocol of management (Specific Aim 2). The protocol will involve intra- and post- operative plasma exchange/pheresis and a uniform immunosuppressive protocol. The primary end-point will be the proportion of patients who are free of death, graft loss and rejection with hemodynamic compromise at one year after transplantation. We hypothesize that 75% of patients will achieve this end-point. Non- sensitized candidates will be studied within a prospective observational protocol under a uniform immunosuppressive regimen (Specific Aim 3) to determine the prevalence of de novo anti-HLA and anti- MICA antibodies. We hypothesize that the development of de novo antibodies will be an independent predictor of more frequent and severe acute rejections. In Specific Aim 4, mechanistic studies will be performed to seek explanation for why some children develop graft injury while others appear to 'accommodate' their graft in the presence of a positive donor-specific cross-match. We hypothesize that three interrelated factors contribute to graft accommodation: 1). Characteristics of the antibody(s) 2). Endothelial cell resistance to antibody mediated damage and 3). Replacement of donor vascular endothelial cells with those of recipient origin leading to endothelial chimerism. Finally, we will investigate the development of a non-invasive marker of humoral rejection; quantitative measurement of cell bound complement activation products. The CTOT-C provides an ideal mechanism for performing the proposed studies and should lead to important new knowledge about antibody mediated graft injury in pediatric heart transplantation. It should provide much needed information for the design of future clinical trials in this field. Relevance: Pediatric heart transplantation remains palliative with high demand for re-transplantation and great economic and social burden. All strategies that could enhance allograft survival will improve the health status of these children and will relieve the burden on the limited donor pool.